Amino acid starvation sensitizes cancer cells to proteasome inhibition

Mizrachy-Schwartz, Sarit; Cohen, Noam; Klein, Shoshana; Kravchenko‐Balasha, Nataly; Levitzki, Alexander

doi:10.1002/iub.377

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…In line with this, a study by Vabulas et al demonstrated that the proteasome plays a crucial role in cell survival during acute amino acid starvation, in part through degradation of preexisting proteins to replenish the pool of amino acids (48). Interestingly, a study by Mizrachy-Schwartz et al found that the tumorigenic cell line MCF7 was much more sensitive to proteasome inhibition during amino acid deprivation than the nontumorigenic cell line MCF10A (49). We thus speculate that a low-calorie diet in mice may increase both the cytotoxicity of isoginkgetin and importantly, its ability to specifically target cancer cells owing to their higher metabolic needs.…”

Section: Discussionmentioning

confidence: 90%

Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

Tsalikis

Abdel-Nour

Farahvash

et al. 2019

Molecular and Cellular Biology

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Protein degradation pathways are critical for maintaining proper protein dynamics within the cell, and considerable efforts have been made toward the development of therapeutics targeting these catabolic processes. We report here that isoginkgetin, a naturally derived biflavonoid, sensitized cells undergoing nutrient starvation to apoptosis, induced lysosomal stress, and activated the lysosome biogenesis geneTFEB. Isoginkgetin treatment led to the accumulation of aggregates of polyubiquitinated proteins that colocalized strongly with the adaptor protein p62, the 20S proteasome, and the endoplasmic reticulum-associated degradation (ERAD) protein UFD1L. Isoginkgetin directly inhibited the chymotrypsin-like, trypsin-like, and caspase-like activities of the 20S proteasome and impaired NF-κB signaling, suggesting that the molecule may display its biological activity in part through proteasome inhibition. Importantly, isoginkgetin was effective at killing multiple myeloma (MM) cell linesin vitroand displayed a higher rate of cell death induction than the clinically approved proteasome inhibitor bortezomib. We propose that isoginkgetin disturbs protein homeostasis, leading to an excess of protein cargo that places a burden on the lysosomes/autophagic machinery, eventually leading to cancer cell death.

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Section: Discussionmentioning

confidence: 90%

Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

Tsalikis

Abdel-Nour

Farahvash

et al. 2019

Molecular and Cellular Biology

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“…Many studies have shown that metabolic differences between cancer and normal cells determine the sensitivity of enzyme therapies, and cell death was also found to occur in both MCF7 and MCF10A cells after arginine deprivation. Therefore, clear cell identification needs to be incorporated to ensure targeted enzyme therapy [ 66 , 71 , 72 ]. To explore the cellular uptake of nanocatalysts, this study was visualized and quantified using GHE loaded with highly fluorescent FITC-Thermozyme (Figs.…”

Section: Resultsmentioning

confidence: 99%

Selective enhanced cytotoxicity of amino acid deprivation for cancer therapy using thermozyme functionalized nanocatalyst

Tang,

Zhang,

Huang

et al. 2024

J Nanobiotechnol

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Background Enzyme therapy based on differential metabolism of cancer cells has demonstrated promising potential as a treatment strategy. Nevertheless, the therapeutic benefit of reported enzyme drugs is compromised by their uncontrollable activity and weak stability. Additionally, thermozymes with high thermal-stability suffer from low catalytic activity at body temperature, preventing them from functioning independently. Results Herein, we have developed a novel thermo-enzymatic regulation strategy for near-infrared (NIR)-triggered precise-catalyzed photothermal treatment of breast cancer. Our strategy enables efficient loading and delivery of thermozymes (newly screened therapeutic enzymes from thermophilic bacteria) via hyaluronic acid (HA)-coupled gold nanorods (GNRs). These nanocatalysts exhibit enhanced cellular endocytosis and rapid enzyme activity enhancement, while also providing biosafety with minimized toxic effects on untargeted sites due to temperature-isolated thermozyme activity. Locally-focused NIR lasers ensure effective activation of thermozymes to promote on-demand amino acid deprivation and photothermal therapy (PTT) of superficial tumors, triggering apoptosis, G1 phase cell cycle arrest, inhibiting migration and invasion, and potentiating photothermal sensitivity of malignancies. Conclusions This work establishes a precise, remotely controlled, non-invasive, efficient, and biosafe nanoplatform for accurate enzyme therapy, providing a rationale for promising personalized therapeutic strategies and offering new prospects for high-precision development of enzyme drugs. Graphical Abstract

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“…These methods are known to be ineffective on tumor cell lines due to the inhibition of proteasome activity and result in an increase in cell death. [ 37 ]…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle Synchronization of the Murine EO771 Cell Line Using Double Thymidine Block Treatment

et al. 2020

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This study shows that double thymidine block treatment efficiently arrests the EO771 cells in the S‐phase without altering cell growth or survival. A long‐term analysis of cell behavior, using 5(6)‐carboxyfluorescein diacetate N‐succinimidyl ester (CFSE) staining, show synchronization to be stable and consistent over time. The EO771 cell line is a medullary breast‐adenocarcinoma cell line isolated from a spontaneous murine mammary tumor, and can be used to generate murine tumor implantation models. Different biological (serum or amino acid deprivation), physical (elutriation, mitotic shake‐off), or chemical (colchicine, nocodazole, thymidine) treatments are widely used for cell synchronization. Of the different methods tested, the double thymidine block is the most efficient for synchronization of murine EO771 cells if a large quantity of highly synchronized cells is recommended to study functional and biochemical events occurring in specific points of cell cycle progression.

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Amino acid starvation sensitizes cancer cells to proteasome inhibition

Cited by 6 publications

References 20 publications

Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

Isoginkgetin, a Natural Biflavonoid Proteasome Inhibitor, Sensitizes Cancer Cells to Apoptosis via Disruption of Lysosomal Homeostasis and Impaired Protein Clearance

Selective enhanced cytotoxicity of amino acid deprivation for cancer therapy using thermozyme functionalized nanocatalyst

Cell Cycle Synchronization of the Murine EO771 Cell Line Using Double Thymidine Block Treatment

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